Syn-2869, -Drug Synthesis Database

【结构式】

【药物名称】Syn-2869

【化学名称】4-[4-[4-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenyl]-2-[4-(trifluoromethoxy)benzyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

【CA登记号】210562-98-4

【分子式】C₃₂H₃₁F₅N₈O₃

【分子量】670.64767

【开发单位】Naeja (Originator), Taiho (Originator)

【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY

合成路线1 合成路线2

合成路线1

1) The reaction of 1-(4-nitrophenyl)piperazine (I) with tert-butyl dicarbonate (II) and triethylamine in dichloromethane gives 4-(4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (III), which is reduced with H2 over Pd/C, yielding the corresponding 4-amino compound (IV). The reaction of (IV) with phenyl chloroformate (V) and triethylamine in dichloromethane affords the carbamate (VI), which by reaction with hydrazine is converted into the semicarbazide (VII). The cyclization of (VII) with formamidine (VIII) and triethylamine in hot 2-methoxyethanol affords the triazolone (IX), which is condensed with 4-(trifluoromethoxy)benzyl bromide (X) by means of Cs2CO3 in DMF, giving the disubstituted triazolone (XI). The deprotection, elimination of the tert-butoxycarbonyl group, of (XI) with HCl yields the monosubstituted piperazine (XII), which is finally condensed with (2R,3S)-oxirane (XIII) by means of LiClO4 in refluxing acetonitrile.

参考文献中间体

【1】 Abel, M.D.; Bathini, Y.; Ha, C.; et al.; Syn-2869, novel broad-spectrum antifungal triazole: Synthesis and structure activity relationships. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-148.
【2】 Fromtling, R.A.; Castañer, J.; Syn-2869. Drugs Fut 1999, 24, 1, 30.
【3】 Ha, C.; Unemi, N.; Nguyen, D.; Furukawa, T.; Sidhu, I.; Daneshtalab, M.; Bathini, Y.; Micetich, R.; Khan, J.; Abel, M.; Salama, S. (Synphar Laboratories Inc.; Taisho Pharmaceutical Co., Ltd.); New triazoles as therapeutic agents for fungal infections. EP 0889881; JP 2000507275; WO 9831675 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	20299	1-(4-nitrophenyl)piperazine	6269-89-2	C₁₀H₁₃N₃O₂	详情	详情
(II)	13214	Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate	24424-99-5	C₁₀H₁₈O₅	详情	详情
(III)	20301	tert-butyl 4-(4-nitrophenyl)-1-piperazinecarboxylate		C₁₅H₂₁N₃O₄	详情	详情
(IV)	20302	tert-butyl 4-(4-aminophenyl)-1-piperazinecarboxylate		C₁₅H₂₃N₃O₂	详情	详情
(V)	13580	1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate	1885-14-9	C₇H₅ClO₂	详情	详情
(VI)	20304	tert-butyl 4-[4-[(phenoxycarbonyl)amino]phenyl]-1-piperazinecarboxylate		C₂₂H₂₇N₃O₄	详情	详情
(VII)	20305	tert-butyl 4-[4-[(hydrazinocarbonyl)amino]phenyl]-1-piperazinecarboxylate		C₁₆H₂₅N₅O₃	详情	详情
(VIII)	15369	Iminoformamide; Methanimidamide	463-52-5	CH₄N₂	详情	详情
(IX)	20307	tert-butyl 4-[4-(5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl]-1-piperazinecarboxylate		C₁₇H₂₃N₅O₃	详情	详情
(X)	20308	4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene	50824-05-0	C₈H₆BrF₃O	详情	详情
(XI)	20309	tert-butyl 4-(4-[5-oxo-1-[4-(trifluoromethoxy)benzyl]-1,5-dihydro-4H-1,2,4-triazol-4-yl]phenyl)-1-piperazinecarboxylate		C₂₅H₂₈F₃N₅O₄	详情	详情
(XII)	20310	4-[4-(1-piperazinyl)phenyl]-2-[4-(trifluoromethoxy)benzyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₂₀H₂₀F₃N₅O₂	详情	详情
(XIII)	13114	1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole		C₁₂H₁₁F₂N₃O	详情	详情

合成路线2

2) The addition of 1-(4-nitrophenyl)piperazine (I) to the chiral oxirane (XIII) as before gives the disubstituted piperazine (XIV), which is hydrogenated with H2 over Pd/C in ethyl acetate, yielding the anilino derivative (XV). The acylation of (XV) with phenyl chloroformate (V) and triethylamine in dichloromethane affords the carbamate (XVI), which is treated with hydrazine to give the semicarbazide (XVII). The cyclization of (XVII) with formamidine (VIII) as before affords the triazolone (XVIII), which is finally condensed with 4-(trifluoromethoxy)benzyl bromide (X) by means of Cs2CO3 in DMF.

参考文献中间体

【1】 Abel, M.D.; Bathini, Y.; Ha, C.; et al.; Syn-2869, novel broad-spectrum antifungal triazole: Synthesis and structure activity relationships. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-148.
【2】 Fromtling, R.A.; Castañer, J.; Syn-2869. Drugs Fut 1999, 24, 1, 30.
【3】 Ha, C.; Unemi, N.; Nguyen, D.; Furukawa, T.; Sidhu, I.; Daneshtalab, M.; Bathini, Y.; Micetich, R.; Khan, J.; Abel, M.; Salama, S. (Synphar Laboratories Inc.; Taisho Pharmaceutical Co., Ltd.); New triazoles as therapeutic agents for fungal infections. EP 0889881; JP 2000507275; WO 9831675 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	20299	1-(4-nitrophenyl)piperazine	6269-89-2	C₁₀H₁₃N₃O₂	详情	详情
(V)	13580	1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate	1885-14-9	C₇H₅ClO₂	详情	详情
(VIII)	15369	Iminoformamide; Methanimidamide	463-52-5	CH₄N₂	详情	详情
(X)	20308	4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene	50824-05-0	C₈H₆BrF₃O	详情	详情
(XIII)	13114	1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole		C₁₂H₁₁F₂N₃O	详情	详情
(XIV)	20312	(2R,3R)-2-(2,4-difluorophenyl)-3-[4-(4-nitrophenyl)-1-piperazinyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol		C₂₂H₂₄F₂N₆O₃	详情	详情
(XV)	20313	(2R,3R)-3-[4-(4-aminophenyl)-1-piperazinyl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol		C₂₂H₂₆F₂N₆O	详情	详情
(XVI)	20314	phenyl 4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenylcarbamate		C₂₉H₃₀F₂N₆O₃	详情	详情
(XVII)	20315	N-(4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenyl)-1-hydrazinecarboxamide		C₂₃H₂₈F₂N₈O₂	详情	详情
(XVIII)	20316	4-(4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one		C₂₄H₂₆F₂N₈O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)